Allogeneic human to human transplant remains the best treatment to replace organs that have failed following disease. The incompatibility between the molecules of the major histocompatibility complex (MHC) of the recipient and donor cells is the main barrier to long-term success of organ transplantation. The induction of tolerance to the allograft has become a major objective and certain tolerance strategies are beginning to be applied clinically. Different populations of Tregs have been described as being capable of inducing tolerance to allogeneic organs. Most of these Tregs are CD4+ Tregs, while CD8+ Tregs are less well defined.
It has been previously described that costimulation blockade of CD40-CD40L interaction, one of the most efficient strategies to prolong organ allograft survival, induces CD8+CD45RClow Tregs cells (called CD8+CD40Ig Tregs) with potent suppressive capacity 1,2). It has been showed that donor-specific CD8+CD40Ig Tregs but not natural CD8+CD45RClow Tregs transferred tolerance to naive transplant recipients. In addition, these cells acted in an unusual way as allograft survival was dependent on their secretion of interferon-γ (IFNγ) to enhance indoleamine 2,3-dioxygenase (IDO) expression by dendritic cells (DC) and graft endothelial cells (EC) (1). It has also been recently showed that the suppressive activity of the CD8+CD40Ig Tregs was mainly performed in the presence of plasmacytoid DCs (pDCs) and that fibrinogen-like protein 2 (FGL2) was involved in the suppression (2).
The requirement for a TCR interaction in the shaping of the regulatory T cell population is an active and ongoing debate. Some studies suggest that TCR specificity and diversity is critical for in vivo function and potency of CD8+ Tregs (3). Different models for CD4+ Tregs have shown that antigen-specific Tregs are more potent suppressor than unrestricted Treg cells. It is also known for CD4+ Tregs that TCR diversity is critical for thymic selection and differentiation and its impact on Treg generation and function has been recently described. High-throughput sequencing has shown that naive Tregs with high TCR diversity expand more efficiently, are more adaptable and more efficient in suppressing Graft versus Host Disease (GVHD) upon adoptive transfer than TCR restricted Tregs. Using Immunoscope®, it has been previously demonstrated that CD8+CD40Ig Tregs accumulated a biased repertoire toward the Vβ11 element (2), suggesting the possibility of a clonal expansion. To date, little is known on the recognition features of this Treg population, or of CD8+ Treg populations in general. The exact role of TCR/MHC/peptide interaction in Treg activity thus remains a topic of debate.
Moreover, there is still a great need for providing efficient therapeutic strategies based on Treg-mediated suppression of immune response against the transplant (such as donor-specific antibodies which are associated with antibody-mediated rejection) thus avoiding the need to use non specific immunosuppressive drugs which have the drawbacks to increase the attack rate of opportunistic diseases (e.g. bacterial, viral or fungal infections) and increase the mortality of transplanted patients.
Van Denderen et al. (4) describes donor peptides that elicit an in vitro proliferative response of total splenocytes (mostly effector CD4+ and CD8+ T cells, B cells, macrophages, NK cells, NKT cells . . . ) from grafted animals that had either tolerated or rejected their allograft. They identified donor peptides that elicit a positive response in recipients that had rejected their allograft, donor peptides that elicit a positive response in recipients that had tolerated their allograft and donor peptides that elicit a positive response in both groups.
It should be noted that peptide 13 described in said article did not elicit any response in rejecting or tolerating recipients. In regards to this article, peptide 13 would never have been selected and used to induce tolerance.
In addition, stimulation of total splenocytes with peptide 14 resulted in activation of the cells from the rejecting recipients and a smaller activation of the cells from the tolerating recipients. This result suggested that this peptide was recognized by cells presents in both recipients but especially in rejecting recipients and thus could not be used to induce tolerance.
Finally, the authors do not identify the subset of cells that is stimulated by the different allopeptides. Given the cell population used for this in vitro assay, it is probable that peptides are recognized by effector cells that represent 90% of the T cells in splenocytes.